Summary of work: Biochemical abnormalities in Down's syndrome (trisomy 21; DS) and Alzheimer's disease (AD) are investigated using analytical techniques. Using GC/MS we reported a 50% increase in the myo-inositol (MI) concentration in cerebrospinal fluid in DS adults. Regional brain MI concentration was measured in Ts65Dn mouse (a partial trisomy 16 model of DS), and elevated MI concentration was found in frontal cortex, hippocampus and brain stem, but not in cerebellum. Also, in this mouse, MI was not elevated in kidney, heart and spleen, whereas liver and skeletal muscle showed increased accumulation. A stable isotope technique was developed to measure MI uptake and turnover in cultured cells. Mouse trisomy 16 cortical neurons (compared with diploid) exhibited higher sodium dependent MI uptake, consistent with the overexpression of the MI transporter gene found on mouse chromosome 16 and human chromosome 21. As MI plays a central role in signal transduction involving phosphoinositides and phospholipases, the defect may be related to mental retardation in DS. Analytical methods were developed to quantitate physostigmine (anticholinesterase) and arecoline (cholinergic agonist) in plasma of human subjects given these drugs in clinical protocols involving positron-emission tomography and cognitive activation. Intravenous infusion schedules were designed on the basis of pharmacokinetic determinations. Additionally, two polyunsaturated molecular species of phosphatidylcholine exhibiting rapid radiolabeled arachidonate incorporation were identified in rat brain, with turnover rates of the order of minutes. These species likely play an important role in signal transduction (Ann Rep Z01 AG 00134-13 LN).